This invention relates to the use of certain pyrazolopyrimidine compounds as sodium channel inhibitors and to the treatment of neuropathic pain by the inhibition of sodium channels. Additionally, this invention relates to novel pyrazolopyrimidine-based compounds that are useful as sodium channel inhibitors.
Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported that sodium channel-blocking agents may also be useful in the treatment of pain, including neuropathic pain; see, for example, Tanelian et al. Pain Forum. 4(2), 75-80 (1995). Preclinical evidence demonstrates that sodium channel-blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is via this mechanism that they are believed to be useful for relieving pain. Consistent with this hypothesis, it has been shown that sodium channels accumulate in the peripheral nerve at sites of axonal injury (Devor et al. J. Neurosci. 132: 1976 (1993)). Alterations in either the level of expression or distribution of sodium channels within an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma.
An increasing body of evidence suggests that a voltage-dependent, tetrodotoxin (TTX)-resistant Na channel, PN3 (Nav1.8), may play a key role in sensitization in neuropathic pain states. Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.
PN3 is a member of a family of voltage-gated sodium channel alpha subunits. Names for this family include SCN, SCNA, and Navx.x. There are currently 10 known members falling into two subfamilies Nav1 (all but SCN6A) and Nav2 (SCN6A). The human channel was cloned by Rabert et al. (Pain 78(2): 107-114 (1998)). PN3 of other species has also been cloned. See, for example, Chen et al., Gene 202(1-2), 7-14 (1997); Souslova et al., Genomics 41(2), 201-209 (1997); Akopian et al., Nature 379(6562), 257-262 (1996).
PN3-null mutant mice exhibit a pronounced analgesia to mechanical noxious stimuli (Akopian A. N. et al., Nature Neurosci., 2(6): 541-548 (1999)). Selective xe2x80x9cknock downxe2x80x9d of PN3 protein in the rat dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury (Porreca et al., Proc. Nat. Acad. Sci., USA, 96: 7640-7644 (1999)). The biophysical properties of PN3 make it ideally suited to sustain repetitive firing of sensory neurons at the depolarized potentials characteristic of injured peripheral nerves. In both human and animal models of neuropathic pain, there is an increased expression of PN3 at the site of peripheral nerve injury (Clare et al., DDT 5: 506-519 (2000); Coward et al., Pain 85: 41-50 (2000)).
Patients with neuropathic pain do not respond to non-steroidal anti-inflammatory drugs (NSAIDS) and resistance or insensitivity to opiates is common. Most other treatments have limited efficacy or undesirable side effects. Mannion et al., Lancet, 353: 1959-1964 (1999) from the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School wrote: xe2x80x9cThere is no treatment to prevent the development of neuropathic pain, nor to adequately, predictably and specifically control established neuropathic pain.xe2x80x9d
PN3 is a promising molecular target for the treatment of neuropathic pain. One of the most attractive features of PN3 is the highly restricted and peripheral nature of its expression. Antisense studies have revealed no overt (particularly CNS-related) adverse effects, consistent with the localized, peripheral distribution of the channel (Novakovic et al., J. Neurosci., 18(6): 2174-2187 (1998)). Additionally, the high activation threshold of PN3 suggests that the channel may be relatively uninvolved in normal nociception. These properties of PN3 present the possibility that selective blockade of this particular voltage-gated sodium channel (VGSC) may offer effective pain relief without the significant side effect liability normally associated with more promiscuous VGSC blocking drugs. The compounds of the invention are potent inhibitors of PN3 channels.
Ohkawa et al. have described a class of cyclic ethers that are of use as sodium channel blockers (U.S. Pat. No. 6,172,085).
Currently, gabapentin is the market leading treatment for neuropathic pain. As with epilepsy, its mechanism of action for pain is unknown. It is a very safe, easy to use drug, which contributes to its sales. Efficacy for neuropathic pain is not impressive, as few as only 30% of patients respond to gabapentin treatment. Carbamazepine is also used to treat neuropathic pain.
In view of the limited number of agents presently available and the low levels of efficacy of the available agents, there is a pressing need for compounds that are potent, specific inhibitors of ion channels implicated in neuropathic pain. The present invention provides such compounds, methods of using them, and compositions that include the compounds.
It has now been discovered that pyrazolopyrimidines are potent inhibitors of sodium channels. In the discussion that follows, the invention is exemplified by reference to the inhibition of sodium channels that are localized in the peripheral nervous system, and in particular those inhibitors that are selective inhibitors of PN3, and are useful for treating neuropathic pain through the inhibition of sodium ion flux through channels that include the PN3 subunit. The focus of the discussion is for clarity of illustration only.
The compounds and methods of the present invention are useful for treating diseases in which blocking or inhibiting one or more PN3 ion channel provides relief from the disease. Of particular interest is the use of the compounds and methods of the invention for treating pain and central or peripheral nervous system disorders. The present invention is of use for treating both inflammatory and neuropathic pain.
The present invention provides compounds which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides compounds, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain.
In one aspect, the present invention provides compounds according to Formula I: 
In Formula I, R1 represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, and substituted or unsubstituted aryl(alkyl). R2 is a member selected from hydrogen and substituted or unsubstituted alkyl. R1 and R2 taken together with the nitrogen atom to which they are optionally joined to form a 4- to 8-membered heterocycloaryl ring. The symbol R3 represents a member selected from hydrogen, substituted or unsubstituted alkyl, halo, amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. The symbol R4 represents a member selected from hydrogen, halo, substituted or unsubstituted alkyl and substituted or unsubstituted aryl. R5 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl. R6 is a member selected from hydrogen, halo, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl. X is either O or S.
In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound provided above.
In yet another aspect, the present invention provides a method for inhibiting ion flux through voltage dependent sodium channels, comprising contacting a cell containing the target ion channels with a compound of the formula provided above.
In still another aspect, the present invention provides a method for the treatment of diseases through inhibition of ion flux through voltage dependent sodium channels, the method comprising treating the host with an effective amount of a sodium channel inhibiting compound of the formula provided above.
Other objects, advantages and embodiments of the invention will be apparent from review of the detailed description that follows.